Cancer chemoprevention and therapy by monoterpenes.

Monoterpenes are found in the essential oils of many plants including fruits, vegetables, and herbs. They prevent the carcinogenesis process at both the initiation and promotion/progression stages. In addition, monoterpenes are effective in treating early and advanced cancers. Monoterpenes such as limonene and perillyl alcohol have been shown to prevent mammary, liver, lung, and'other cancers. These compounds have also been used to treat a variety of rodent cancers, including breast and pancreatic carcinomas. In addition, in vitro data suggest that they may be effective in treating neuroblastomas and leukemias. Both limonene and perillyl alcohol are currently being evaluated in phase I clinical trials in advanced cancer patients. The monoterpenes have several cellular and molecular activities that could potentially underlie their positive therapeutic index. The monoterpenes inhibit the isoprenylation of small G proteins. Such inhibitions could alter signal transduction and result in altered gene expression. The results of a new gene expression screen-subtractive display-have identified or confirmed several up- or downregulated genes in regressing mammary carcinomas. For example, these regressing tumors overexpress the mannose 6-phosphate/IGF II receptor. The product of the gene both degrades the mammary tumor mitogen IGF II and activates the cytostatic factor TGF-beta. These and other alterations in the gene expression of mammary carcinomas lead to a G1 cell cycle block, followed by apoptosis, redifferentiation, and finally complete tumor regression in which tumor parenchyma is replaced by stromal elements. It is likely that monoterpenes prevent mammary cancer during their progression stage by mechanisms similar to those that occur during therapy. In contrast, prevention of mammary cancer by polycyclic hydrocarbons such as 7,12-dimethylbenz[a]anthracene occur by the induction of detoxifying phase II hepatic enzymes.